The effective delivery of a pharmaceutical agent to an active site and achieving an acceptable rate of release of pharmaceutical agents are enduring problems in developing and improving pharmaceutical therapies. In particular, it is well recognized that the gastro-intestinal tract of vertebrate animals provides a number of physical and chemical barriers against the successful administration of therapeutic agents. For example a therapeutic agent must be able to withstand the attack of endogenous enzymes, gastric acidity and intestinal alkalinity without losing activity, and then still penetrate across the gastrointestinal mucosa, into the blood stream and to the site where activity is required. Moreover, all of this must take place at an appropriate rate to ensure the correct therapeutic dosage is delivered.
In the past, many approaches have been adopted to attempt to solve these problems. For example, administration of a particularly high dose of active agent can be effective in ensuring that at least some of the agent reaches the desired active site without degradation. This approach to administration of enteric agents is clearly problematic and not economical. In some instances it can be appropriate for simple mechanical carriers such as pressed tablets or enteric coatings to be provided in order to improve enteric tolerance of the agent concerned, and to regulate the rate of drug release. There has also been considerable research recently to develop liposomes or lipid microbubbles that can be used to encapsulate active agents. These approaches have not been successful in all circumstances.
Micro and nanoparticles which can encapsulate pharmaceutical agents in order to provide protection and regulate their rate of release were described in U.S. Pat. No. 5,352,461. This patent relates to the self-assembling particle drug delivery systems formed from 2,5-diketo-3,6-di(4-succinylaminobutyl)piperazine, which are claimed to be pH sensitive so that they therefore disassemble and release the entrapped pharmaceutical agent, at high pH. Other particles which are suggested as being able to encapsulate agents such as insulin and heparin and protect these molecules from gastric acidity and stomach enzymes, and to release the agents into the bloodstream, were proposed in International Patent Publication No. WO 88/01213. Self-assembling pH titratable particulate systems, based upon the self-assembling properties of bis-amide dicarboxylic acids are described in the work of Bergeron et al., J. Amer. Chem. Soc. 1995, 117, 6658-6665. These particles also share the properties of stability at low pH and instability as pH increases.
International Patent Publication No. WO 96/29991 describes the formation of self-assembling particles that are based upon polyaminoacids, more particularly polyleucine-glutamate. These particles which are prepared from natural amino acids have the property of controlled particle size and are stable over a wide pH range.
Particles for entrapment of pharmaceutical agents, and particularly peptides or proteins, can also be formed by polyelectrolyte complexation of various anionic polymers with cationic polymers. Anionic polymers may include natural substances such as sodium alginate, carboxymethyl cellulose, guaran, polyglutamic acid and their derivatives, amongst others. Examples of cationic polymers include polylysine and gelatin. Other polycations and polyanions are described in detail within European Patent No. 671169, U.S. Pat. Nos. 4,835,248 and 5,041,291, which are incorporate herein by reference in their entirety.
Unfortunately, there are limitations to the effectiveness of particles for pharmaceutical delivery according to the prior art, as it has been found in many cases that these particles rapidly release the entrapped pharmaceutical agent upon parenteral or enteral administration. As a result, efforts have been made to develop stabilised microparticles by the use of glutaraldehyde cross-linking. This method of cross-linking however suffers from the disadvantage that it can result in the modification of the entrapped pharmaceutical agent, which is clearly undesirable. A further disadvantage is that such cross-linking is optimally performed under alkaline conditions, the same conditions under which many of these pH-sensitive particles will rapidly release the entrapped pharmaceutical agents.
It is apparent, therefore, that practical methods of particle stabilisation that are suitable for use with pH-sensitive particles and which can be performed with little or no risk of modification of the entrapped pharmaceutical agent are greatly to be desired. In particular, methods that can be used for delivery of pharmaceutical agents are highly desirable.